Treatments for systemic amyloid diseases have been held back by lack of information on the structures and causes of aggregation of the disease agents. These agents are the elongated, unbranched amyloid fibers formed by proteins having propensity for aggregation. The fibers accumulate in organs which eventually fail. In contrast, the increasingly successful attack on cancer, infectious, and metabolic diseases is rooted in part in the availability of information on the structures of the disease targets, permitting design of effective chemical interventions. In previous work we have developed a procedure for inhibiting the formation of amyloid fibers. This first step is application of our computer algorithm which identifies the short Velcro-like sequence segments that drive formation of amyloid fibers. We have applied this algorithm to find over 100 such segments in disease- related proteins, and have verified that such segments themselves form amyloid fibers, and closely related microcrystals. The second step is X-ray structure determination of these microcrystals, which reveal the atomic basis of fiber formation. The third step is to use the resulting atomic structure as a platform for the design of inhibitors to stop fiber formation. This overall procedure is robus and ready to produce inhibitors of fibers found that cause light-chain (AL) and transthyretin (TTR) systemic amyloidosis. In our research, we will validate particular segments of immunoglobulin light chains and transthyretin as the causes of aggregation, and based on their atomic structures, design inhibitors of aggregation. These inhibitors will be tested for their abilty to halt fiber formation in vitro, and in animal models. In principle, the same methods can be used to develop inhibitors for other systemic amyloid diseases.